Angiogenesis is a phenomenon of generating a new capillary vessel, which is a normal physiological function, as well as a pathological function caused by various diseases. Angiogenesis has a deep connection with growth and transfer of solid cancer, rheumatic arthritis, diabetic retinopathy, psoriasis, or the like [Billington, D.C., Drug Design and Discovery, 8:3-35 (19910]. In 1971, Judah Folkman of the Medical College of Harvard University, USA, suggested a novel concept of treating solid cancer by inhibiting angiogenesis. [Folkman, J., New Eng. Med., 185:1182 (1971)].
Recently, the clinical importance of therapeutic agents as a means of controlling angiogenesis has been emphasized, and various researches on angiogenesis have been performed. According to clinical results of anticancer medicines using angiogenesis inhibitors, in particular, it is expected that they cause little problems caused by general anticancer medicines, including adverse effect and tolerance. In other words, an angiogenesis inhibitor does not directly act on tumor cells, but acts on endothelial cells of a living organism, and thus, the problem of tolerance does not probably occur, and a synergistic anticancer effect is expected by a therapy in combination with conventional anticancer medicines which have been employed up to the present.
Various fumagillin compounds inhibiting angiogenesis have been reported. For example, it is known that fumagillin having angiogenesis inhibiting action is produced by culturing Aspergillus fumigatus, a productive strain isolated from a soil sample. [Eble, T. E., Hanson, F. R.
Antibiotics & chemotherapy, 1, 54 (1951), Eble, T. E., Hanson, F. R. J.
Bact., 58, 527 (1949)] [Ingber, G., Fujita, T., Kishimoto, S., Sudo, K., Kanmaru, T., Bre, H., Folkman, J., Nature 248, 555(1990)]
Besides, EP-A-354787, EP-A-357061, JP-A01-233275 and EP-A-415294 have been disclosed; and 6-amino-6-deoxy fumagillol [Chem. Pharm. Bull., (1992), 40, 575], 6-acyl, 6-O-sulfonyl, 6-O-alkyl and 6-O-(N-substituted carbamoyl) fumagillol [Chem. Pharm. Bull., (1992), 40, to 96] are reported to have angiogenesis inhibiting action. However, continuous development of angiogenesis inhibitors having less toxicity and more excellent effect is further required.